basal insulin t1 & t2 1...2018/10/11 · basal insulin t1 & t2 3 above 10% trends among...

1Basal Insulin T1 & T2

Irl B. Hirsch, MDEndocrinologist

University of Washington,Seattle, Washington

Steven V. Edelman, MDClinical Professor Of Medicine

University Of California, San DiegoFounder and Director

Taking Control Of Your Diabetes

Initiation, Titration And Maintenance Of Basal Insulin In Type 1 Versus Type 2 Diabetes: An Important Foundation To Successful

Insulin Management

Comparing and Contrasting Type 1 and Type 2 Diabetes…

Sometimes It’s Like Comparing Apples to Oranges

….and Sometimes It’s Like Comparing Apples to Apples

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} Misperceptions and Physical Appearance} Incidence and Prevalence} Hereditary Influence} Etiology and “Natural History”} Characteristics and Associated Conditions } Treatment Strategies} Approaches to basal insulin management strategies

Type 1 and Type 2 Diabetes Are Very Different

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Incidence and Prevalence of Type 1 vs Type 2 Diabetes

Type 1 Type 2Number in the US

1,250,000 31,000,000

Diagnosed Every Day in the US

110 6,000

Edelman SV. Taking control of your diabetes: a patient oriented book on diabetes. Fifth Edition Professional Communications Inc., Greenwich, CT. 544 pages, 2017.

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Type 1 Race/Ethnicity

81% White

Beck RW, Tamborlane WV, Bergenstal RM, Miller KM, Dubose SN, Hall CA. The T1D Exchange Clinic Registry. J Clin Endocrinol Metab. 2012; 97:4383-9.

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Trends Among Adults With Type 2 Diabetes in the U.S. 1990

Mokdad et al., Diabetes Care 2000;23:1278-83.

No Data

Less than 4%

4% -6%

Above 6%

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www.diabetes.org

Above 10%

Trends Among Adults With Type 2 Diabetes in the U.S. 2018

Over 300 billion dollars a year!

No Data Less than 4% 4% - 6% Above 6%

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Risk of Developing Type 1 vs Type 2General Population 0.3% 8-11%

If you have a sibling with T1D/T2D

4% ~30%

If your mother has T1D/T2D 2 – 3% ~30%

If your father has T1D/T2D 6 – 8% ~30%

If you have an identical twinwith T1D/T2D

~50% 100%


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Natural History of Type 2 Diabetes

Macrovascular complicationsMicrovascular complications

Insulin resistance

Prediabetes Type 2 Diabetes

Insulin secretion Postprandial glucose

Fasting glucose

Progression of Dysglycemia

Prediabetes and Early Type 2 Diabetes: Generally Asymptomatic

Diagnosis of Type 2 Diabetes Typically Delayed

Years to Decades

Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789I


Natural History and Cause of Type 1 Diabetes Autoimmune condition

Genetic predisposition

Damage to the cells of the pancreas

Pre-diabetes Diabetes

Time = months to a few years

100% Insulin making cells of the pancreas

Putative Trigger

Immune System Dysfunction

Circulating Auto Antibodies (ICA, GAD)

Symptoms

Pettus J, Edelman SV. (2013) Adjunctive Therapies. In The American Diabetes Association/JDRF Type 1 Diabetes Sourcebook (319-340). VA: American Diabetes AssociationI

} Usually average weight} Dx usually before age 25} Beta cell destruction} Autoimmune condition} High rate of hypothyroidism

and celiac disease} 5-10% of all PWD

JeremyPettusDiagnosed Age 15

•Mary Tyler Moore•Chris Dudley•Charlie Kimball•Jay Cutler•Nick Jonas •Sharon Stone•Gary Hall Jr. •Phil Southerland

Type 1

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Age at Diagnosis of T1D


You can get type 1 diabetes at any age!

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Ø The most missed diagnosis in diabetes

Ø Type 1 diabetes can occur at any age

Ø Slower beta-cell destruction (may respond briefly to oral agents)

Ø Typically does not have features of the Metabolic Syndrome

Ø Blood test positive for type 1 diabetes (GAD auto antibodies)

Latent Autoimmune Diabetes in Adults (LADA)

Gary Hall Jr.Olympic Gold MedalistWorld Record Holder

Edelman SV. Taking control of your diabetes: a patient oriented book on diabetes. 5th Edition Professional Communications Inc., Greenwich, CT. 544 pages, 2017.

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Generic and Trade Names: InsulinGeneric Name Trade Name

Fast-Acting Insulin RegularU-500 RegularAspartFaster Acting AspartGlulisineLispro (U-100 and U-200)Follow on biologic lisproInhaled Insulin

Humulin R, Novolin RHumulin R U-500 NovoLogFiaspApidraHumalogAdmelogAfrezza

Basal Insulin Intermediate-Acting:NPH

Long-Acting:DetemirGlargine (U-100)Glargine (U-300)*Degludec (U-100/200)*

Follow on biologicglargine (U-100)

Humulin NNovolin NPH

LevemirLantusToujeo*Tresiba*

BasaglarInformation taken from the PDR Guide and Package Inserts S

Shortcomings of Basal Insulins Include:

} Hypoglycemia resulting in:◦ Insulin under-dosing◦ Insufficient glycemic control

} Weight gain} Inconsistent insulin action…leading to inconsistent blood glucose

levels} Not enough flexibility with timing of injections} Insufficient duration of action…therefore, requiring a minimum of 1

and, sometimes, 2 injections/day} Large volume injections required for some patients

Expert Opin. Biol. Ther. (2014) 14(6):7909-88I


Two New Basal Insulins Recently Added to Our List of Options

Both approved by the FDA and now available for patients1. U-300 glargine a long-acting basal insulin

2. U-100 and U- 200 degludec a long-acting basal insulin

Toujeo prescribing information. Bridgewater, NJ: sanofi, US; 2015 http://products.sanofi.us/toujeo/toujeo.pdfTresiba prescribing information 2015. http://www.novo-pi.com/tresiba.pdf

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U-300 Glargine• A more concentrated (300 units/ml) form of traditional glargine

insulin (100 units/ml)• Compared to U-100 glargine, U-300 glargine has less intra-subject

variability, less hypoglycemia and less weight gain.• Flat, stable and prolonged action up to 30 hours (needs 5 days to

equilibrate...tell your patients!)• In the clinical trials patients on U-300 glargine with type 1 and type 2

diabetes may require a dose 12 to 18% higher than previous U-100 glargine (still with less hypo and less weight gain).

• Pen holds 450 units• New Pen holds 900 units and can give 150U at one time

Riddle MC et al. Diabetes Care. 2014;37:2755-2762; Yki-Järvinen H et al. Diabetes Care. 2014; Published ahead of print: doi: 10.2337/dc14-0990Bolli GB et al. Poster presented at EASD 2014: P947; Bajaj H. Oral presentation at CDA 2014: #14; Home P et al. Abstract presented at EASD 2014: 0148Bajaj H et al. Poster presented at CDA 2014: P112; Matsuhisa M et al. Poster presented at EASD2014: P975; Terauchi Y et al. Poster presented EASD 2014: P976

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PK/PD Profile with Glar U-300 vs Glar U-100

Becker RH, et al. Diabetes Care. 2015:4;639-643.

3

2

1

0

20

10

0

0 6 12 18 24 30 36

Insu

lin

Co

nce

ntr

atio

n(µ

U/m

L)

Glu

cose

Infu

sio

n R

ate

(mg

/kg

/min

)

25

15

5 LLOQ

Time (h)

0 6 12 18 24 30 36

Glar U300 0.4 U/kg, N=16Glar U100 0.4 U/kg, N=17

U-300 glargine has a more even and prolonged PK/PD profile

May need 13 to 17% more than previous dose of glargineI


Glucose Infusion Rate In Subjects With Type 1 Diabetes Insulin Glargine U-300

50 T1D subjects underwent two euglycemic clamp studies after 6 daysof receiving Insulin glargine U-300

Becker RHA, et al. Diabetes Obes Metab. 2015; 17(3): 261-267I

U-100 and U-200 Insulin Degludec• Available as either 100 units/ml (~detemir) or 200 units/ml• Long duration of action up to 42 hours (needs 5 days to

equilibrate...tell your patients!)

• Peakless

• Low intra-subject variability

• Less hypoglycemia and variability compared to U-100 glargine

• Disposable pens hold a maximum of 300 (U-100) and 600(units)

• 160 units can be given at one time.Owens et al. Diabetes Metab Res Rev. 2014;30:104-119.Heise T et al. Diabetes Obes Metab. 2012;14:944-950.Heise T et al. Diabet Med. 2002;19:490-495.Jonassen I et al. Pharm Res. 2012;29:2104–2114.Press release: http://www.novonordisk.com/include/asp/exe_news_attachment.asp?sAttachmentGUID=a1b5d012-c7cb-4b56-9525-b9c779d01dde Accessed December 15, 2014.

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A b Glucose clamp study in patients with T2DM (n = 49).c Glucose clamp study in patients with T2DM (n = 16).

1. Heise T, et al. Diabetes Obes Metab. 2012;14:944-950.2. Heise T, et al. Diabetes. 2012;61(suppl 1):A91 [abstract 349-OR].

U-100 Formulation1,b U-200 Formulation2,c

GIR

, mg/

kg/m

in

0

23

45

1

160 4 8 12 20 24Time, hours

0.8 U/kg

0.4 U/kg0.6 U/kg

GIR

, mg/

kg/m

in

0

23

45

1

160 4 8 12 20 24Time, hours

0.6 U/kg

Pharmacodynamics of Insulin Degludeca U-100 and U-200 in Patients with T2DM: Same time course of action

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2018 ADA Basal Insulin Recommendations

American Diabetes Association Dia Care 2018S

First Goal in Starting Basal Insulin in Type 2 Diabetes: Correct Fasting Hyperglycemia

100

200

300

PG

(m

g/dL

)

0800 1200 1800 0800

A1c ~7%

Adapted with permission from Cefalu WT. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:1-11.

A1c ~9%

Second Goal: Control Postprandial Hyperglycemia If A1c Still >7% (or above individual goal)

A1c below 7%

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} Only 1 injection per day is typically required

Combination Therapy: Adding Basal Insulin to Oral Agents an Effective Strategy to Initiate Insulin Therapy In T2D

} Convenience (usually given at night or first thing in the morning)

} Slow, safe, and simple titration} Low dosage needed compared to a full insulin regimen} Limited weight gain - especially compared to insulin only

regimens} Effective improvement in glycemic control by suppressing

hepatic glucose production

} No need for mixing different types of insulin

Edelman SV, Henry RR. Diagnosis and management of type 2 diabetes.12th Edition. Professional Communications, Inc., Greenwich, CT. 288 pages, 2014.

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Second Pitfall in Initiating and Titrating Basal Insulin(First one is too slow titration after starting)

Not Paying Attention To The Bedtime Glucose Value

1. Ask the patient to do paired testing (test at bedtime and again the next morning).

2. If the bedtime BG is high, then that needs to be addressed by either lifestyle modification including reduced caloric consumption and/or post dinner exercise.

3. Other options include prandial insulin or a GLP-1 RA


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} An ADA/EASD consensus algorithm for the initiation and adjustment of basal insulin:

Appropriate Self-Titration is Critical to the Success of Insulin Therapy

Check fasting glucose daily and increase dose by:Increase 10 to 15% or 2 to 4 units once or twice a week until

fasting glucose is in target range

Start with a long-acting basal insulin

Initiate at 10 units/day or 0.2 units/kg/day

ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes.Nathan et al. Diabetes Care. 2018

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Increase by 1 to 2 Units every 1 day until FPG < 120 mg/dL

Simple Daily Self-Titration Option*(much easier to follow by the patient than the once or twice a

week method)

*Adjust dose subsequently to patient’s need.†Dosage was not increased that week if there were any episodes of documented hypoglycemia (<72 mg/dL) during the preceding week. FPG, fasting plasma glucose.Gerstein HC et al. Diabet Med. 2006;23:736-742.

EXAMPLELess than 100: decrease by 2 unitsBetween 100 and 150: no changeOver 150: increase by 2 units

The goal can be individualized

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Self Titration Clinic FormBasal insulin Morning

20 1

2 140 90

90 140

2

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} Initial A1c was 9.5%} Eventually started on metformin, sequentially followed by a sulfonylurea a DPP-4 inhibitor and a SGLT-2 inhibitor over a 4 year period.

} PMH: HTN, CHF, dyslipidemia, arthritis and ED} Exercises irregularly and “tries to follow a diet”} A1c now is 8.0%

Case: 61 Year Old Overweight Male With Type 2 Diabetes For 8 years

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} Staggered testing results (asked to test one to two times a day at different times)

Case continued

Time Blood glucose range Blood glucose average

Pre-Breakfast 148 – 229 mg/dL (~175 mg/dL)

Pre- Lunch 111 – 182 mg/dL (~147 mg/dL)

Pre- Dinner 91 – 155 mg/dL (~139 mg/dL)

Bedtime 148 – 231 mg/dL (~184 mg/dL)

No reports of hypoglycemia

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Which of the following would you suggest if he was your patient?

A Start a pre-mixed insulin at dinner time

B Initiate basal insulin

C Start a GLP-1 RA

D Start pioglitazone

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} U-300 Glargine was added at night (20 units)} and titrated up to 120 units over the next 10 weeks} I asked him to test 2x/day (bedtime and the next morning)} It is important to make sure the patient is not going to bed high

Case continued

Pre-Breakfast 82 – 155 mg/dL (~122 mg/dL)Pre- Lunch ---- ----Pre- Dinner ---- ----

Bedtime 128 – 183 mg/dL (~145 mg/dL)

} A1c dropped to 7.1%, no hypoglycemia. Gained 2 lbs in 3 months

} Oral agents can be continued unless hypoglycemia occurs during the day, in which case the sulfonylurea should be reduced or withdrawn

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If you control the blood glucose at a particular time of the day, the subsequent number will also improve. Make one

change at a time!

Domino Effect


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} Currently on maximum doses of 3 oral agents: metformin, SFU and a DPP-4 inhibitor.

} A1c > 8.5% for the past 2 years

} She was started on basal insulin and the HCP titrated her dose based on her morning glucose value. Her current dose is 78 units

} Current SMBG (mg/dl) below:

Case 62 year old female with type 2 diabetes for 12 years

Pre-Breakfast Pre-Lunch

Pre-Dinner

Bedtime

Monday 243 ---- ---- ---

Tuesday 221 ---- --- ----

Wednesday 54 ---- ---- ---

Thursday 267 ---- --- ----S

Which of the following is the single most likely explanation for her low glucose value of 54 mg/dl?

A She did an unusual amount of exercise that morning

B She had a much lighter dinner than usual the night before

C She took twice the amount of basal insulin by accident

D The value from her glucose meter was not correct

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} She was asked to do some paired testing (bedtime and the next morning for several days in a row

Case continued

Pre-Breakfast Pre-Lunch

Pre-Dinner Bedtime

Friday 201 ---- ---- 244

Saturday 192 ---- --- 154

Sunday 82 ---- ---- 239

Monday 212 ---- --- 267

} Her basal dose has been titrated up too high and the main issue is that she is going to bed too high.

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Clinical Pearls: Combination Therapy with Basal Insulin

-1- Start with 10 to 20 units (also consider FBS, weight)

-2- The key to success is frequent follow up after initiation to avoid “failure” (most patients will need 40 to 70 units/day)

-3-Have the patient follow a self-titration regimen and return to clinic or follow up in some other manner (phone, fax, email, telehealth, etc.) relatively soon

-4-You can usually limit SMBG to only once a day in the morning but check at bedtime once in awhile to make sure the pt. does not need pre dinner fast acting insulin or a GLP1-RA


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IS or Intermittent Sensing Is Excellent For Type 2s

Goes on easily12 hour warm up timeLasts 10 daysSwipe to get a number

Has trend arrowsNo calibrationNo alerts or alarmsNo sharing feature

swipeS

First Step is to make sure

the basal rate is correct!

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1. Unexpected highs2. Unexpected lows3. Carb:Insulin ratio

not working consistently4. Correction Factor not working

consistently5. Not responding to insulin and

exercise consistently

Despite Following all of the Rules

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A1c Goal = <8.5%

A1c Goal = <8.0%

A1c Goal = <7.5%

A1c Goal = <7.0%

Only ~30% of Type 1s Reach ADA Goal of an A1c Less than 7%


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Physiologic Insulin, Glucagon and Amylin Secretion

LiverPancreas

Portal Vein

Systemic Circulation

InsulinAmylin

Glucagon

Beta Cell

Alpha CellPettus J, Edelman SV. (2013) Adjunctive Therapies. In The American Diabetes Association/JDRF Type 1 Diabetes Sourcebook (319-340). VA: American Diabetes Association

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Insulin(µU/mL)

Glucose(mg/dL)

Physiologic Insulin Secretion and Glucose Levels In Healthy Subjects

15010050

07 8 9 10 11 12 1 2 3 4 5 6 7 8 9A.M. P.M.

Basal Glucose

Time of Day

5025

0 Basal Insulin: HGO(40 to 60% of TDD)

Breakfast Lunch Dinner

Bolus Insulin (40 to 60% of TTD)

Edelman SV, Henry RR. Diagnosis and management of type 2 diabetes. 12th Edition. Professional Communications, Inc., Greenwich, CT. 288 pages, 2014.

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Continuous Glucose Monitoring Devices Currently Available in the United States

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Reasons For A High FBS: Single vs. Continuous Glucose Monitoring

050

100150200250300350

9:00PM

11:00PM

1:00AM

3:00AM

5:00AM

7:00AM

9:00AM

Home glucose monitor Continuous Monitoring

Glu

cose

(mg/

dL) Going to bed too high

Rebounding from a hypo

Need more basal

Dawn Phenomenon

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Testing The Basal Rate In Type 1 DiabetesTesting Overnight1. Ask the patient have an early dinner, make sure the post prandial

BS is between 140 and 180mg/dl (may need a correction dose) with a horizontal trend arrow

2. Fast until the next morning3. If not on a CGM then he/she needs to test the BS every few hours

Testing During The Day (different day than testing pm)1. Ask the patient if he/she can skip breakfast and fast as long as

possible. 2. If patient wants to eat a small breakfast then make sure the post

breakfast BS is between 140-180mg/dl with a horizontal trend arrow


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. . . ...

..

. .2 hours

150 mg/dl

80 mg/dl

135 mg/dl

gluc

ose

0.75 U/hr B A S A L

94 mg/dl

Testing A Basal Segment in T1D: Foundation of any Insulin Regimen

145 mg/dl

2 hours 2 hours

105 mg/dl

fasting

https://mysugr.com/basal-rate-testing/ S


39 year female with T1D for 2 years on an insulin pump (0.6 U/hr). Her main problem is that she goes to bed with a good BS level and then wakes up with a high value. What is the most likely cause?

A Not bolusing enough for her bedtime snack

B Early morning resistance to insulin (dawn phenomenon)

C Eating a snack at 3am without any insulinD Gastroparesis S

} Improved glycemic control◦ More precise, physiologic insulin delivery◦ Greater ability to handle dawn phenomenon, stress and other

conditions that alter insulin requirements

} In some situations (but not all) freedom and flexibility in lifestyle◦ Eliminate multiple daily injections (1 stick every 3 days) Very

easy to respond to CGM results◦ Reduce restrictions on eating, exercise and sleeping patterns;

could have the same benefits with MDI◦ Greater flexibility with sports, travel, work schedule and other

activities (not with water sports)

Insulin Pumps: Advantages

Walsh JA, Roberts R. Pumping Insulin 5th edition. 2011.

Edelman SV. Taking control of your diabetes: a patient oriented book on diabetes. Fifth Edition Professional Communications Inc., Greenwich, CT. 544 pages, 2017. S

25 y/o male with T1D on insulin detemir. Good values at bedtime and high in the morning. He also c/o occasional night sweats.What is/are the possible cause(s) for the high morning BS?

A Bolusing fast-acting insulin at bedtime

B Too much basal insulin

C Going to the 24 hour gym at midnightD All of the above S


34:00 16:00 20:00 24:00 4:00 8:0012:008:00

Time

Basal infusion

Bolus Bolus Dual Wave Bolus

Variable Basal Rate Capability(Total daily basal dose/24) - (10 to 20%)

1

2

Breakfast Lunch Dinner

Plas

ma

insu

lin

Edelman SV. Taking control of your diabetes: a patient oriented book on diabetes. Fourth Edition Professional Communications Inc., Greenwich, CT. 544 pages, 2017.

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Smart Phone Clarity App

Mean glucose value

Standard Deviation

Time in Range

24 hour multiday profileI

Is this T1D on too much basal?

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Testing the overnight basal doseSame patient fasting from 6pm until 9am

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Is this T1D on too much basal?

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Same pt. fasting from 9pm until 7am

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A. Decrease the basal insulinB. Switch the U-100 glargine for U-300 glargine or

degludecC. Have a larger bedtime snackD. Do not exercise after 7pm

What is the best treatment option to help this patient with his overnight values?

32 year old male with T1D on glargine U-100 at bedtime and a fast acting analog with meals and for correction doses.

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Summary and Conclusions

Type 1 and Type 2 Diabetes are very different conditions including the approach to basal insulin therapy

In Type 2 diabetes self titration is important to reach an adequate FBS and paired testing is important o make sure the bedtime glucose value is in range

In Type 1 diabetes the basal dose should be tested by overnight and daytime fasting.

CGM is the standard of care in T1D and will shortly be used more and more in type 2 Diabetes

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basal insulin t1 & t2 1...2018/10/11 · basal insulin t1 & t2 3 above 10% trends among...

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